Perspectives
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PERSPECTIVES but, like surgery, could not eradicate metastatic TIMELINE cancer. Effective treatment for most patients needed to reach every organ in the body. Drugs, biological molecules and immune- Chemotherapy and the war on cancer mediated therapies have therefore become the focus for current efforts to cure cancer. From the first experiments with nitrogen mustard 60 Bruce A. Chabner and Thomas G. Roberts Jr years ago to current attempts to develop drugs for specific cancer-related targets, researchers Abstract | The era of chemotherapy began Of the many challenges of medicine, none has from multiple disciplines have joined together in the 1940s with the first uses of nitrogen had a more controversial beginning and none in the search for more effective cancer drugs. mustards and antifolate drugs. Cancer drug has experienced more hard-fought progress Over time, the development of anticancer development since then has transformed than the treatment and cure of cancer. therapies, based at first on empirical observa- from a low-budget, government-supported Although the neoplastic process has been rec- tions, has become increasingly dependent on research effort to a high-stakes, multi-billion ognized for centuries, little was known about an understanding of human tumour biology. dollar industry. The targeted-therapy the biological mechanisms of transformation revolution has arrived, but the principles and tumour progression until the advent of The first efforts (1940–1950) and limitations of chemotherapy discovered molecular medicine in the latter half of the The beginnings of the modern era of by the early researchers still apply. This twentieth century. Before 1950, therapy chemotherapy can be traced directly to the article chronicles the history of modern remained largely the province of the surgeon. discovery of nitrogen mustard as an effective chemotherapy and identifies remaining Radiation therapy became a valuable tool for treatment for cancer1 (see TIMELINE). In challenges for the next generation of control of local and regional disease after 1960, 1942, Louis Goodman and Alfred Gilman researchers. with the invention of the linear accelerator, and colleagues were recruited by the United Timeline | The history of chemotherapy Louis Goodman and Alfred Gilman use The National A combination of Studies by Brian nitrogen mustard to treat Chemotherapy cyclophosphamide, Druker lead to FDA The FDA approves a patient with non- Program begins at the methotrexate and The NCI introduces approval of imatinib bevacizumab Hodgkin’s lymphoma and National Cancer The Food and Drug Vincent DeVita fluorouracil (CMF) was ‘disease oriented’ mesylate (Glivec) for (Avastin), the first demonstrate for the first Institute (NCI); a Administration (FDA) and colleagues shown to be effective screening using 60 chronic myelogenous clinically proven anti- time that chemotherapy systematic programme approves the cure lymphomas as adjuvant treatment cell lines derived leukaemia, a new angiogenic agent, can induce tumour for drug screening alkylating agent with combination for node-positive from different types paradigm for targeted for the treatment of regression. commences. cyclophosphamide. chemotherapy breast cancer. of human tumour. therapy in oncology. colon cancer. 1942 1948 1955 1958 1959 1965 1970 1972 1975 1978 1989 1992 2001 2004 Syndey Farber uses Roy Hertz and Min Chiu Li Combination Emil Frei and colleagues The FDA approves The FDA approves Researchers at Harvard University antifolates to demonstrate that chemotherapy demonstrate that cisplatin for the paclitaxel (Taxol), define mutations in the epidermal successfully induce methotrexate as a single (POMP regimen) is chemotherapy given after treatment of ovarian which becomes the growth factor receptor that confer remissions in agent can cure able to induce long- surgical removal of cancer, a drug that first ‘blockbuster’ selective responsiveness to the children with acute choriocarcinoma, the first term remissions in osteosarcoma can would prove to have oncology drug. targeted agent gefitinib, indicating lymphoblastic solid tumour to be cured by children with ALL. improve cure rates activity across a broad that molecular testing might be leukaemia (ALL). chemotherapy. (adjuvant chemotherapy). range of solid tumours. able to prospectively identify subsets of patients that will respond to targeted agents. George Hitchings and Gertude Elion synthesize the purine analogue 6-mercaptopurine. NATURE REVIEWS | CANCER VOLUME 5 | JANUARY 2005 | 65 PERSPECTIVES States Department of Defense to examine the Emil Frei and colleagues demonstrated that potential therapeutic value of a series of toxins high doses of methotrexate with leucovorin developed for chemical warfare. In May 1942, prevented recurrence of osteosarcoma follow- Goodman and Gilman, both pharmacologists ing surgical removal of the primary tumour, at the Yale School of Medicine, convinced their establishing the principle of adjuvant collaborator, Gustav Lindskog, a thoracic sur- therapy 8,9.Although this therapy was associ- geon, to treat a patient with non-Hodgkin’s ated with bone-marrow toxicity, the toxic lymphoma with nitrogen mustard2.They effects were reversible, whereas the antitumour proposed that this reagent might destroy a effects cured patients of their cancer. lymphoid tumour, based on autopsy findings The basis for selective effects of these from soldiers dying of exposure to sulphur agents against tumour cells versus normal mustard gas during the First World War. tissue was not apparent from the early labo- These victims had profound lymphoid ratory or clinical experiments. It would take hypoplasia and myelosuppression. Reasoning Figure 1 | Sydney Farber working at his 10 years after the initial studies by Farber that measured doses of a similar agent might microscope. Courtesy of the Dana-Farber and colleagues for Michael Osborn and Cancer Institute, Boston, Massachusetts, USA. cause regression of a lymphatic tumour3, Frank Huennekens to discover, in 1958, that Goodman and Gilman carried out experi- the antifolate drugs specifically inhibi- ments in mice bearing a transplanted lym- ted dihydrofolate reductase (DHFR)10,11. phoid tumour. When they observed a marked The antifolates Subsequently, Joseph Bertino (FIG. 2),David level of tumour regression, they convinced A second approach to drug therapy of can- Goldman, Robert Schimke and Bruce Lindskog to inject the closely related com- cer began shortly after the Second World Chabner provided further insight into the pound ‘nitrogen mustard’,a simple but highly War, when Sydney Farber (FIG. 1),a patholo- mechanisms of methotrexate12, leading to reactive molecule, into the bloodstream of a gist at Harvard Medical School and at the the model for our current understanding of patient with advanced non-Hodgkin’s lym- Children’s Hospital in Boston, investigated the pharmacological principles of cancer phoma and airway obstruction. The medi- the effects of folic acid on patients with chemotherapy. The action of methotrexate astinal and lymphatic masses of the patient leukaemia. This vitamin, which had been depends on active transport into cells regressed. This remission, however, lasted identified by Lucy Wills in 1937 to be the through the reduced-folate transporter 1 only a few weeks, and disease again pro- factor that was deficient in patients with (RFT-1), its conversion to a long-lived intra- gressed, but the principle was established that megaloblastic anaemia4,seemed to stimu- cellular polyglutamate, and its binding to drugs could be administered systemically to late proliferation of acute lymphoblastic DHFR, which leads to inhibition of the syn- induce tumour regression. leukaemia (ALL) cells when administered thesis of thymidylate and purines and the The same scientists next pursued studies to children with this cancer. Farber’s collab- induction of apoptosis (FIG. 3). to define the molecular action of the mus- oration with Harriett Kilte and the medici- Cellular defects in any of these steps can tard compound, demonstrating its forma- nal chemists at Lederle Laboratories led lead to drug resistance. Mutations in RFT-1, tion of an alkylating intermediate, the to the synthesis of folate analogues — amplification or mutation of DHFR, loss of ethyleneimmonium ring, which reacted first aminopterin and then amethopterin polyglutamation, and defects in the apop- with electron-donating sites on proteins (methotrexate) — which Farber adminis- totic pathway have all been shown to lead to and nucleic acids. The principle was estab- tered to children with ALL in the late 1940s loss of efficacy13,14.Methotrexate was also lished that tumours might be more suscep- (REF. 5).By blocking the function of folate- the first drug for which pharmacokinetic tible to toxins than normal tissues, requiring enzymes, these agents became the analysis was routinely used to monitor drug although the reasons for this were not first drugs to successfully induce remission clearance and identify patients at risk of understood. The discovery that the reagent in children with ALL. Remissions were severe toxicity15.Methotrexate is still pri- formed a covalent bond with DNA was brief, but the principle was clear — antifo- marily used to treat patients with ALL, as made through later studies that demon- lates could suppress proliferation of malig- well as those with certain lymphomas, strated specific sites of alkylation on purine nant cells, and could thereby re-establish osteosarcoma and choriocarcinoma.